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Oral transmission of Candida albicans between partners in HIV-infected couples could contribute to dissemination of fluconazole-resistant isolates.

Dromer F, Improvisi L, Dupont B, Eliaszewicz M, Pialoux G, Fournier S, Feuillie V.

Unite de Mycologie, Centre National de Reference des Mycoses et des Antifongiques, Paris, France.

BACKGROUND: Fluconazole resistance has emerged among Candida albicans isolates and has been associated with the prolonged or repeated use of the drug. This study was designed to discover whether transmission of oral isolates could occur between sexual partners and thereby explain fluconazole resistance in patients never treated with the drug. MATERIALS AND METHODS: The oral flora of 10 HIV-infected couples (five heterosexual and five homosexual) were studied. In vitro susceptibility testing and genotyping (restriction fragment length polymorphism with EcoRI and HinfI) were used to delineate strain relatedness for 230 clones (five clones per sample, one to four samples per patient). RESULTS: The genetic diversity of the clones with one DNA subtype was specific to a given patient or a given couple, except in one case in which unrelated patients shared clones of the same genotype. The persistence of clones between partners was stable over time in six out of 10 couples and only transient in one couple. Fluconazole resistance in isolates from patients who had never been treated with azoles was associated in three patients with the first episode of oropharyngeal candidiasis and treatment failure. CONCLUSION: The observation that couples tended to share genetically indistinguishable clones was highly suggestive of transmission between partners. This phenomenon may, in part, explain the pathogenesis of oropharyngeal candidiasis and the increased frequency of fluconazole resistance both in vitro and in vivo.

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Clinical pharmacokinetics of fluconazole in superficial and systemic mycoses.

Debruyne D.

Laboratory of Pharmacology, University Hospital Center, Caen, France.

The bis triazole agent fluconazole is used widely in the treatment of superficial and deep mycoses. A single oral dose of fluconazole 150 mg gives a mean long term clinical cure rate of 84 +/- 5% and is considered a valuable alternative to other topical antifungal drugs for vaginal candidiasis. A clinical cure rate of 90.4% for oropharyngeal candidiasis was obtained with 100mg daily for a minimum of 14 days; however, as for the other azoles the rate of relapse was large (40%) in immunocompromised patients. A daily dose of 100mg for at last 3 weeks gave satisfying outcomes for oesophageal candidiasis. Most patients (71 to 86%) with signs and symptoms of urinary tract candidiasis show beneficial clinical results when given oral fluconazole 50mg for several weeks. Fluconazole 50 to 150 mg given for weeks or months results in over 90% clinical cure or improvement for cutaneous mycosis including tinea, pityriasis, cryptococcosis and candidiasis. Prolonged (6 to 12 months) fluconazole 150 mg once a week is needed to treat onychomycosis successfully. Higher oral doses (200 to 400 mg daily) for long periods are generally used to treat deep mycoses such as meningitis, ophthalmitis, pneumonia, hepatosplenic mycosis and endocarditis. Fluconazole is effective for treating the fungal peritonitis which can complicate continuous ambulatory peritoneal dialysis (CAPD). A regimen of 50 mg intraperitoneally or 100 mg orally was used in these patients with impaired renal function. The dosage schedules used to treat disseminated fungal infections due to systemic mycoses with different or multiple foci of infections vary widely, with doses of 50 to 400 mg given orally or intravenously for between 1 week and several months. The most recent clinical reports have investigated the use of prophylaxis with fluconazole 100 to 400 mg daily, in immunocompromised patients. Fluconazole is found in body fluids such as vaginal secretions, breast milk, saliva, sputum and cerebrospinal fluid at concentrations comparable with those determined in blood after single or multiple doses. There is an excellent linear plasma concentration-dose relationship, but the mycological and clinical responses do not appear to be well correlated with the dose. A total maximum daily dose of 1600 mg is recommended to avoid neurological toxicity. Data from pharmacokinetic studies conducted in patients, mainly those with AIDS, and using a 1-compartment model give very constant parameters similar to those obtained in healthy individuals. Bioavailability, measured in HIV-positive patients and those with AIDS, exceeded 93% for tablets, suspension and suppositories. The time to reach peak plasma concentrations (tmax) was 2.4 to 3.7 hours. The peak plasma drug concentration (Cmax) obtained after a 100 mg oral dose was 2 mg/L. Areas under the concentration-time curve (AUC) obtained in different studies all correlate well with the dose (r = 0.926). The AUC determined after 200 and 25 mg suppositories were similarly well correlated. Hypochlorhydria does not affect the absorption of fluconazole, neither does food intake, race (Japanese or Caucasian) or gastrointestinal resection. Binding to plasma protein is low (11.14%) and is increased to 23% in cancer patients. Fluconazole is rapidly distributed to the tissue, where it accumulates. Tissues fall into 1 of 4 groups of increasing drug concentration: blood, bone and brain have the lowest concentrations, and spleen has the highest. The volume of distribution (Vd) remains stable at 46.3 +/- 7.9L and is considered to be an 'invariant' parameter across species. Fluconazole is poorly metabolised and is mainly eliminated unchanged in the urine. The percentage of the dose recovered in the urine in 48 hours is close to 60%. Concentrations in the urine are high and the half-life (t1/2) is long (37.2 +/- 5.5h) in patients, mainly those with AIDS, which is not significantly different from the t1/2 (31.4 +/- 4.7 hours) in healthy individuals. (ABSTRACT TRUN

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Isolation of Candida species on media with and without added fluconazole reveals high variability in relative growth susceptibility phenotypes.

Schoofs A, Odds FC, Colebunders R, Ieven M, Wouters L, Goossens H.

Department of Microbiology, University of Antwerp, Belgium.

Mouthwashes from human immunodeficiency virus-positive individuals were sampled for yeasts by direct plating on a differential agar medium with and without added fluconazole and via enrichment broths with and without added fluconazole. The colonies of the yeasts isolated were tested for relative growth in the presence of single concentrations of itraconazole and fluconazole. Among 258 culture plates containing yeasts obtained via different isolation routes from 86 yeast-positive samples, 33 (12.7%) of the plates showed unexpectedly high colony-to-colony variation in relative growth. Intercolony variation was seen in 41 (47.7%) of the 86 isolates when relative growth data were analyzed for all colonies of an isolate tested, regardless of the medium used for isolation. The prevalence of relative growth variability with the azoles was highest for Candida glabrata (100% of 13 isolates), followed by Candida krusei (60% of 5 isolates) and Candida albicans (40% of 53 isolates), and the visual patterns of variability seen in scatter plots of the data showed species specificity. Relative growth phenotypes generally tended to be stable for each yeast colony in subcultures, whether or not the medium used for subculture contained antifungal agents. DNA fingerprinting of stable and variable C. albicans isolates showed changes in band patterns detected with the probe Ca3, suggesting that the variability may have resulted from selection of different subtypes of the yeasts during the isolation procedure. These findings suggest that the yeasts isolated from single clinical samples were often not clonal in nature. The relative growth test revealed colony variability more readily than conventional susceptibility testing.

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In vitro activities of terbinafine in combination with fluconazole and itraconazole against isolates of Candida albicans with reduced susceptibility to azoles.

Barchiesi F, Falconi Di Francesco L, Scalise G.

Institute of Infectious Diseases and Public Health of the University of Ancona, Italy. cmalinf popcsi.unian.it

A checkerboard microdilution method was applied to study the in vitro interaction of terbinafine with either fluconazole and itraconazole against 30 strains of Candida albicans. Synergy was observed in 40% of the terbinafine-fluconazole interactions and in 43% of the terbinafine-itraconazole interactions, while antagonism was not observed. Even when only additivity was achieved, the combinations still showed beneficial effects since at least twofold reductions in the MICs of both drugs were found in 100% of the terbinafine-fluconazole interactions and in 76% of the terbinafine-itraconazole interactions.

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Prevalence and antifungal susceptibility of vaginal yeasts in outpatients attending a gynecological center in Ancona, Italy.

Arzeni D, Del Poeta M, Simonetti O, Offidani AM, Lamura L, Balducci M, Cester N, Giacometti A, Scalise G.

Institute of Infectious Diseases and Public Health, University of Ancona, Italy.

Between February 1993 and May 1994 we studied the prevalence of fungal vulvovaginitis among women attending the Obstetric and Gynecology Clinic of the University of Ancona. Out of the 222 patients, 18 (8.2%) women had symptomatic vaginitis and 24 (10.8%) were carriers. Candida albicans was the species most frequently isolated (44.2%), followed by Torulopsis glabrata (28%) and Saccharomyces cerevisiae (16.2%), from symptomatic and carrier patients. The activity of acid proteinase was determined for C. albicans isolated from both symptomatic and carrier patients. All 13 carriers showed low activity for aspartyl proteinase (score 1+), while 5 of 6 symptomatic patients showed higher activity (score 2+), with a significant difference (p = 0.026). In general, isolates of T. glabrata and S. cerevisiae were less susceptible in vitro to fluconazole than isolates of C. albicans. We did not find any differences in fluconazole MIC results among the C. albicans strains isolated from symptomatic and carrier patients. On the other hand, the fluconazole MICs of T. glabrata and S. cerevisiae isolates showed statistically significant differences between symptomatic and carrier patients (p = 0.009 and p = 0.000, respectively). The differences in proteinase secretion between the isolates from symptomatic and carrier patients suggest a correlation between proteinase production and vaginal candidiasis caused by C. albicans. Torulopsis glabrata, however, was found to be the most common causative agent of vaginitis (7 out 19 episodes), followed by C. albicans (6 out of 19 episodes). Due to the varying patterns of antifungal susceptibility, mainly to fluconazole for the yeast isolates considered in this study, an in vitro susceptibility testing program might be useful for monitoring the outcome of this infection.

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Eight-year surveillance of non-albicans Candida spp. in an oncology department prior to and after fluconazole had been introduced into antifungal prophylaxis.

Kunova A, Trupl J, Demitrovicova A, Jesenska Z, Grausova S, Grey E, Pichna P, Kralovicova K, Sorkovska D, Krupova I, Spanik S, Studena M, Koren P, Krcmery V Jr.

National Cancer Institute Department of Microbiology, Department of Medicine, Bratislava, Slovak Republic.

From 1989 until 1996, during the last 8 years, the proportion of Candida (C.) krusei, and other non-albicans Candida spp. isolated from surveillance cultures and from sterile body sites, was analyzed among 13,758 admissions in a National Cancer Institute. During these admissions a total of 9,042 isolates were prospectively collected from surveillance cultures, and 126 from blood cultures. The proportion of C. krusei among all organisms was 12.7% to 16.5% in 1989 through 1991, i.e., before fluconazole was introduced into prophylactic protocols. After the introduction of fluconazole into prophylaxis in acute leukemia in 1992 the incidence of C. krusei was 7.9% to 8.6% during 1994 to 1996. After 5 years of using this drug for prophylaxis, the incidence of C. krusei was lower than before this drug was introduced in our institute. Among yeasts, the most frequently isolated pathogen was still Candida albicans (72.2% of all isolated fungal organisms). Among molds, Aspergillus spp. was the most frequently isolated agent. Analyzing the etiology of proven fungal infections (fungemias) confirmed by positive blood cultures, C. albicans was the most common causative organism in 53.8% of cases. The incidence of fungemia due to Torulopsis (C.) glabrata and C. krusei before and after fluconazole introduction did not change. Of 126 organisms isolated from blood cultures, there was no increase in T. (C.) glabrata or C. krusei after introduction of fluconazole for prophylaxis and therapy, and the quoted 6.4% of fungemic episodes remained stable with an incidence of 1 fungemia/year since 1991. The proportion of C. krusei and C. glabrata among Candida spp. was decreasing in our center between 1989 and 1996. Also, the proportion of non-albicans Candida spp. among isolates decreased from 25.7% in 1990 to 11.9% in 1996.

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Prospective study of fluconazole therapy in systemic neonatal fungal infection.

Wainer S, Cooper PA, Gouws H, Akierman A.

Department of Paediatrics, Baragwanath Hospital, University of the Witwatersrand, South Africa.

BACKGROUND: Standard neonatal systemic antifungal therapy with amphotericin B and flucytosine can be associated with toxicity, drug resistance and the need for prolonged venous access. There is consequently a need for alternative treatment options. OBJECTIVES: To assess the efficacy and safety of fluconazole in the treatment of systemic neonatal fungal infections. METHOD: Open, nonrandomized evaluation of fluconazole treatment in 20 consecutively enrolled neonates with systemic fungal infection. RESULTS: Clinical and microbiologic cure was achieved in 12 of 19 (63%) of infants treated. One additional infant received prior amphotericin B therapy and is included for assessment of side effects. One infant with Torulopsis glabrata infection failed treatment. Six infants died of Gram-negative bacterial infection and other intercurrent medical problems. CONCLUSION: Fluconazole appeared to be safe and effective for treatment of systemic candidal infection in the neonate although more data are required in very low birth weight infants.

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Granulocyte colony stimulating factor therapy of experimental cryptococcal meningitis.

Graybill JR, Bocanegra R, Lambros C, Luther MF.

Department of Medicine, University of Texas Health Science Center at San Antonio, USA.

Cryptococcal meningitis was induced in mice using intracerebral injection of Cryptococcus neoformans. Beginning either 3 days before or 1 day after infection, mice were treated with human recombinant granulocyte colony stimulating factor (hGCSF). In high doses hGCSF reduced the brain tissue burden of C. neoformans but had no effect on survival. The effect of hGCSF was dependent on size of the infecting dose and time of administration. A large innocula of C. neoformans, or when hGCSF was initiated after infection, there was no added benefit. Some groups of mice also received low doses of fluconazole beginning 1 day after infection. Fluconazole both prolonged survival and reduced brain tissue counts of C. neoformans. Combined cytokine/fluconazole therapy was superior to either agent given alone. These studies suggest that hGCSF can add to the efficacy of fluconazole therapy in murine cryptococcosis, and suggest that polymorphonuclear leucocytes contribute to host defence in cryptococcal meningitis. The relative potency of fluconazole appears greater than hGCSF.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9292420&dopt=Abstract fluconazole Diflucan